This invention relates to bioerodible porous compositions for the sequestration and sustained delivery of active agents, particularly pharmaceutical active agents.
Successful treatment of a variety of conditions is limited by the fact that agents known to effectively treat these conditions may have severe side effects, requiring low dosages to minimize these side effects. In other instances, the therapeutic agents may be very labile, or have very short half-lives requiring repeated administration. In still other instances, the long term administration of a pharmaceutical agent may be desired.
In all these cases, the ability to deliver a controlled dosage in a sustained fashion over a period of time may provide a solution. One method of doing so that has received a fair amount of attention is the sequestration and subsequent controlled release of active agents into and from porous compositions.
A number of publications describe the use of nondegradable porous microbeads. For example, U.S. Pat. No. 4,690,825 to Won describes delivery vehicles comprised of a polymeric bead, preferably made of polystyrene, or poly(methyl methacrylate) having a rigid, substantially non-collapsible network of pores with an active ingredient held within the network, for use in a method to provide controlled release of the active ingredient. The delivery vehicles can be polymerized by a process in which the active ingredient also comprises the porogen during formation of the network of pores. The beads may be dried to obtain a powder-like substance comprised of beads which retain the porogen within the network of pores. U.S. Pat. No. 5,145,675 to Won describes the use of a porogen in the preparation of polymer beads preferably made of polystyrene, or poly(methyl methacrylate) having a rigid, substantially non-collapsible network of pores. Active agents are then diffused into the porous beads from an external solution. However, both of these compositions are nondegradable and are thus only useful in topical applications where removal is not necessary. Clearly, for systemic applications where porous microparticles are implanted in an appropriate body site it is essential that the polymer microspheres be biodegradable.
Heretofore, major activity in the development of biodegradable microspheres has been concentrated on porous microspheres constructed from lactide/glycolide copolymers as described by Sato et al.(1988), Pharm. Res. 5: 21-30, or by Supersaxo et al. (1993), J. Controlled Release 23, 157-164. However, the preparation of these hollow microspheres requires the use of organic solvents such as methylene chloride which must be subsequently removed so that only a few parts per million remain, a very difficult task. Also, the bioerosion of lactide/glycolide copolymers is relatively slow. Further, even though lactide/glycolide copolymers have obtained FDA approval for certain uses, they are not GRAS ("generally regarded as safe") materials and for this reason, extensive toxicological studies are necessary before new uses are approved.
Thus, there exists a need to develop bioerodible, porous compositions that can be prepared in an aqueous environment, into which sensitive therapeutic agents can be easily and reproducibly incorporated and from which they can be released in an active state. It is further desirable that the materials used to make the compositions be GRAS ("generally regarded as safe") materials. Although there has been no reported work dealing with preparation of porous microspheres that can be prepared in an aqueous environment, there has been a great deal of work on solid porous particles that can be prepared in an aqueous environment. That work can be generally divided into work dealing with the incorporation of living cells, and work dealing with the incorporation of antigens and proteins.
U.S. Pat. No. 5,116,747 to Moo-Young et al. describes the immobilization of cells and other biologically active materials within a semipermeable membrane or microcapsule composed of an anionic polymer such as alginate induced to gel in the presence of calcium and/or a polymeric polycation such as chitosan. U.S. Pat. No. 4,663,286 to Tsang et al. describes the encapsulation of solid core materials such as cells within a semipermeable membrane, by suspending the core material in a solution of a water-soluble polyanionic polymer, preferably alginate salts, forming droplets, and gelling the polyanion with a polyvalent polycation such as a polypeptide, a protein or a polyaminated polysaccharide, preferably polylysine, polyarginine, or polyornithine. This patent further teaches controlling the porosity and permeability of the disclosed compositions to molecules ranging from about 60,000 to about 900,000 daltons by changing the degree of hydration of the polymer. Incubation in saline or chelating agents increases hydration and expands the gels, whereas incubation in calcium chloride contracts the gel mass. Increases in charge density of the polycationic membrane generally produces smaller pores. Increases in the molecular weight of the polycationic polymer generally produce a thicker, less permeable membrane. U.S. Pat. No. 4,803,168 to Jarvis describes the encapsulation of core materials such as cells, enzymes, antibodies, hormones, etc. within a semipermeable membrane or microcapsule composed of an aminated polymeric inner layer such as chitosan ionically bound to an anionic polymeric outer layer such as polyglutamic or polyaspartic acid, and having a porosity of about 80,000 daltons.
A number of publications describe the incorporation of antigens and proteins into calcium alginate microparticles. For example, Bowersock et. al. (1996), J. Controlled Release 39: 209-220, describe development of oral vaccines using an alginate microsphere system and Downs et. al. (1992), J. Cell. Physiol. 152: 422-429 describe the release of growth factors from calcium alginate beads. However, entrapment efficiency was very low and typically, more than 90% of the active agent is not incorporated. Because many of these agents are very expensive, and in some cases high concentration of the active agent in the microsphere is desired, improved methods for preparing drug-loaded microspheres are needed.
A publication by Wheatley et. al. (1991), J. Appl. Polymer Sci., 43: 2123-2135, describes a method for improving entrapment efficiency in alginate/polycation nicrospheres. In this method a diffusion-filling technique is used where blank calcium alginate beads are coated twice with small amounts of a polycation and protein then loaded into these capsules by stepwise diffusion from solutions of increasing drug concentration. This is then followed by a final coating with a polycation. This is a laborious and time-consuming process that requires a number of steps, i.e. empty alginate bead formation, precoating with a polycation, multistep diffusion of drug into the bead and final coating with a polycation. Even using this complex procedure, a maximal loading of only 30 wt % could be achieved.
The disclosures of these and other publications referred to throughout this application are incorporated herein by reference.